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Abstract:

The present invention provides an aqueous ophthalmic solution comprising
an effective amount of ketorolac which comprises carboxymethyl cellulose
in an aqueous solution which provides increased visual acuity in users
and wherein said concentration of carboxymethyl cellulose is selected to
provide an increased absorption of ketorolac in the eye of a patient
which is at least 130% greater than the absorption of a comparative
aqueous ketorolac ophthalmic solution having the same concentration of
ketorolac.

Claims:

1. A topical aqueous ophthalmic solution comprising ketorolac
tromethamine, mixtures of carboxymethyl cellulose, containing no
preservative and having a pH within the range of approximately 6.8-7.4.

3. The topical aqueous ophthalmic solution of claim 1 wherein the
ketorolac tromethamine is present in a concentration of approximately
0.40-0.45 percent by weight/volume of total solution.

4. The topical aqueous ophthalmic solution of claim 1 wherein the
carboxymethyl cellulose is a combination of medium and high viscosity
sodium carboxymethyl cellulose.

5. The topical aqueous ophthalmic solution of claim 1 wherein the
ketorolac tromethamine is present in a concentration of 0.45 percent by
weight/volume.

6. The topical aqueous ophthalmic solution of claim 5 having a pH between
of 6.8.

7. The topical aqueous ophthalmic solution of claim 5 wherein the
concentration of carboxymethyl cellulose is from 0.2 to 2 percent by
weight.

8. The topical aqueous ophthalmic solution of claim 7 wherein the
concentration of carboxymethyl cellulose is 0.5% by weight/volume.

9. The topical aqueous solution of claim 5 wherein the solution is
surfactant and chelator free.

10. The topical aqueous solution of claim 8 for use in treatment of
ocular pain associated with postoperative photorefractive keratectomy.

11. The topical aqueous solution of claim 5 wherein the ophthalmic
solution improves the visual acuity in a patient of at least one line of
improvement.

12. The topical aqueous solution of claim 5 further comprising a mixture
of medium and high viscosity sodium carboxymethyl cellulose, sodium
chloride, sodium citrate dehydrate, sodium hydroxide, hydrochloric acid
and purified water and wherein the solution improves the visual acuity of
a user.

13. The topical aqueous solution of claim 5 wherein the combination of
carboxymethyl cellulose and ketorolac increases the absorption in the eye
of a patient more than a solution of ketorolac alone.

14. The topical aqueous solution of claim 1 wherein the ketorolac
tromethamine is present as a racemic mixture of R-(+) and S-(-)-ketorolac
tromethamine.

15. The topical aqueous solution of claim 5 wherein the viscosity is from
10 to 30 cps.

16. The topical aqueous solution of claim 6 wherein the mixture of
carboxymethyl cellulose is present in the amount of 0.5% percent by
weight.

17. The topical aqueous solution of claim 5 wherein the solution may be
administered before or after eye surgery to prevent ocular pain.

18. The topical aqueous solution of claim 5 wherein the solution
increases healing time of the eye after eye surgery in comparison to
ketorolac solutions containing a preservative.

[0002] This invention relates to pharmaceutical compositions. More
particularly, this invention relates to topical ophthalmic solutions
comprising 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid,
otherwise known as ketorolac, and the use of ketorolac for treating or
preventing ocular pain.

[0004] Ketorolac tromethamine 0.5% (w/v) ophthalmic solution, available
from Allergan, Inc., under the tradeneme ACULAR®, is a safe and
effective NSAID with proven analgesic and anti-inflammatory activity. The
most common adverse event associated with the use of the 0.5% ketorolac
formulation is ocular irritation, primarily burning and stinging upon
instillation. Ketorolac tromethamine 0.4% (w/v) ophthalmic solution,
under the tradename ACULAR LS®, has shown improved bioavailability
and less stinging on instillation than ACULAR®, but there remains a
need for an improved ketorolac tromethamine formulation with greater
bioavailability and greater tolerability, minimized ocular surface
toxicity, improved patient comfort, increased retention time of the
active ingredient and improved wound healing capabilities during use.

[0005] It is one object of this invention to provide a ketorolac
formulation for instillation in the eye to eliminate or reduce ocular
irritation, to improve tolerability, compliance, duration and effect of
ketorolac, to allow for dosing from four times daily to twice daily, and
to increase the effectiveness of treatment by being free of benzalkonium
chloride or other preservatives.

[0006] It is another object of the invention to improve bioavailability
and increase the ocular absorption of ketorolac yet provide an aqueous
solution having an optimized concentration of ketorolac.

[0007] It is another object of the invention to extend the effects of
ketorolac and allow for a decrease in required daily dosage.

[0008] It is another object of the invention to provide reduction of
inflammation associated with cataract surgery and reduction of pain
associated with cataract surgery in comparison to other ketorolac
formulations.

[0009] It is another object of the invention to create a ketorolac
formulation with improved wound healing capabilities.

[0010] Other objects of this invention will become apparent from a reading
of the present specification.

BRIEF DESCRIPTION OF DRAWINGS

[0011] FIG. 1 shows the ocular pharmacokinetics of the results in Example
7 of the increased and prolonged ketorolac exposure in the aqueous humor
of the 0.45% w/v ketorolac solution in comparison to ACULAR LS®;

[0012] FIG. 2 shows the results of FIG. 1 in table form of Cmax, AUC and
percent relative bioavailability of the ocular pharmacokinetics in
Example 7 of the aqueous humor relative bioavailability of 0.45% w/v
ketorolac solution in comparison to ACULAR LS®;

[0013] FIG. 3 shows the ocular pharmacokinetics of the results in Example
7 of the increased and prolonged ketorolac exposure in the iris-ciliary
body of 0.45% w/v ketorolac solution in comparison to ACULAR LS®;

[0014] FIG. 4 shows the results of FIG. 3 in table form of Cmax, AUC and
percent relative bioavailability of the increased and prolonged exposure
in the iris ciliary body of 0.45% w/v ketorolac solution in comparison to
ACULAR LS®;

[0017] The present invention provides an aqueous ophthalmic formulation
comprising an effective amount of ketorolac but having an optimized
concentration of ketorolac in comparison other commercially available
ketorolac products. The aqueous ophthalmic solution of the present
invention comprises carboxymethyl cellulose, e.g. sodium carboxymethyl
cellulose, having a pH within the range of from about 6.8 to 7.4, which
is comfortable when topically applied to the eye of a patient, wherein
the concentration of carboxymethyl cellulose and, preferably, the pH, is
selected to provide an increased absorption of ketorolac in the eye of a
patient as compared to a comparative ketorolac solution that differs only
in not including the carboxymethyl cellulose. That is, the absorption of
ketorolac may be 130% or greater than the absorption of a comparative
aqueous ketorolac ophthalmic solution having the same or higher
concentration of ketorolac.

[0018] More preferably, the aqueous ophthalmic solution of this invention
has a pH within the range of from 6.8 to 7.4, particularly 6.8.

[0019] More preferably, the aqueous ophthalmic solution of the present
invention has a concentration of carboxymethyl cellulose of from about
0.2 to about 2 percent, by weight, even more preferably from about 0.5 to
1.5 percent, by weight, and most preferably about 0.5% w/v.

[0020] Even more preferably, the aqueous ophthalmic solution of the
present invention comprises a mixture of medium viscosity and high
viscosity sodium carboxymethyl cellulose.

[0021] More preferably, the aqueous ophthalmic solution of the invention
comprises an effective amount of ketorolac of from 0.25 to 0.50 percent,
by weight, or about 0.45 percent, by weight.

[0022] More preferably, the aqueous ophthalmic solution of the invention
has a viscosity of from 5 to 50 cps, preferably from 10 to 30 cps.

[0023] It has been surprisingly discovered that optimizing the
concentration of ketorolac tromethamine reduces the occurrence of adverse
events while maintaining clinical efficacy. Additionally, it has been
discovered that the optimized concentration of ketorolac tromethamine in
combination with carboxymethyl cellulose offers surprising and clear
benefits in terms of formulation in that no preservative, chelating
agent, and surfactant are required for formulation. Thus, finding a way
to increase the absorption of ketorolac benefits the patient who can use
a solution having an optimized concentration of ketorolac and obtain
similar results in terms of efficiency as compared to a ketorolac
solution having a higher concentration of ketorolac.

[0024] Thus, this invention relates to an aqueous topical ophthalmic
composition comprising 0.25 to 0.50 percent by weight, more preferably
from 0.35% to 0.45% by weight and most preferably about 0.45% ketorolac
tromethamine by weight/volume. The present invention also contains from
0.2 to 2 percent by weight, more preferably from 0.5 to 1.5 percent by
weight and most preferably about 0.5% w/v percent of medium and high
molecular weight sodium carboxymethyl cellulose. Another aspect of this
invention relates to a method of treating or preventing ocular pain in a
person comprising topically administering to said patient a sterile
composition comprising from 0.25 to 0.50 percent, by weight, more
particularly from 0.35% to 0.45% by weight, or about 0.45% w/v ketorolac
tromethamine in combination with from 0.2 to 2 percent, by weight,
preferably from 0.5 to 1.5 percent by weight, and most preferably 0.5%
percent by weight/volume, sodium carboxymethyl cellulose and mixtures
thereof.

[0025] While not intending to limit the scope of this invention in any
way, of particular interest in relationship to this invention is the use
of aqueous topical ophthalmic compositions of 0.45% (w/v) ketorolac
tromethamine for the treatment of ocular pain, especially for the
treatment of ocular pain in postoperative photorefractive keratectomy
(PRK) surgery patients which improves healing. It is surprising that the
lower concentration of ketorolac as compared to the Acular® product,
discussed herein, would reduce the incidence of adverse events and
enhance comfort while maintaining clinical efficacy. Two drops (0.1 mL)
of 0.5% ketorolac tromethamine ophthalmic solution instilled into the
eyes of patients 12 hours and 1 hour prior to cataract extraction
achieved measurable levels in 8 of 9 patients' eyes (mean ketorolac
concentration 95 ng/mL aqueous humor, range 40 to 170 ng/mL). Ocular
administration of ketorolac tromethamine reduces prostaglandin E2
(PGE2) levels in aqueous humor. The mean concentration of PGE2
was 80 pg/mL in the aqueous humor of eyes receiving vehicle and 28 pg/mL
in the eyes receiving 0.5% ketorolac tromethamine ophthalmic solution.

[0027] During the reformulation of Allergan's marketed Acular LS®
product (0.40% w/v ketorolac), it was surprisingly found that a test
formulation containing 0.45% ketorolac tromethamine and sodium
carboxymethyl cellulose (NaCMC) exhibited significantly better ocular
absorption in rabbits than did the currently marketed product, i.e.
Acular LS®.

[0028] Since the viscosities of the two test solutions were virtually
identical, the mechanism for achieving increased ocular penetration
compared to the control formulation cannot be accounted for only by the
viscosity of the test solutions. In fact, a comparison of two identical
carboxymethyl cellulose-containing solutions which differ only in having
viscosity of 11 and 22 cps shows similar absorption of ketorolac into the
aqueous humor. While not wishing to be bound by theory, it is believed
that there is a functional relationship between the sodium carboxymethyl
cellulose and either the ketorolac or some component of the ocular
surface that facilitates absorption of ketorolac.

[0029] All of the aqueous topical ophthalmic solutions of this invention
are contemplated for use in treating or preventing ocular pain.
Preferably, all of the solutions of this invention are contemplated for
use when said ocular pain is a result of photorefractive keratectomy
surgery (PRK).

[0030] One important aspect of this invention is that the solutions of the
present invention have a concentration of ketorolac tromethamine which is
optimized to reduce side effects, while maintaining clinical efficacy in
treating ocular pain. As such, the concentration of ketorolac
tromethamine in compositions related to this invention is preferably from
0.35% to 0.45% w/v, most preferably the concentration of ketorolac
tromethamine in the aqueous topical ophthalmic solution of this invention
is 0.45% ketorolac tromethamine, by weight.

[0031] Carboxymethyl cellulose (CMC) is a carboxymethyl derivative of
cellulose formed by the reaction of cellulose with alkali and
chloroacetic acid. As a result of said reaction, carboxymethyl groups are
bound to some of the hydroxyl groups of the glucopyranose units that make
up the backbone of cellulose. The degree of substitution of carboxymethyl
varies from about 0.6 to 0.95 per glucopyranose unit. CMC is used in
aqueous solutions usually as the sodium salt to increase viscosity.

[0032] Carboxymethyl cellulose is available in various molecular weights.
Low molecular weight carboxymethyl cellulose has a Mw of about 90,000
daltons and a 2% solution thereof will have a viscosity of about 1.1 cP
at 25° C. Medium weight carboxymethyl cellulose has a Mw of about
250,000 daltons. High molecular weight carboxymethyl cellulose has a Mw
of about 700,000 daltons and a 2% solution will have a viscosity of about
12 cP at 25° C.

[0033] For the purpose of the present invention, it is desirable to use a
mixture of medium and high molecular weight sodium carboxymethyl
cellulose. For example, from 25/75 to 75/25 carboxymethyl cellulose,
preferably from 30/70 to 70/30 and most preferably about 35/65
medium/high molecular weight sodium carboxymethyl cellulose or most
preferably a ratio of 0.325/0.175.

[0034] The fact that the concentration of ketorolac tromethamine in
compositions related to this invention achieves greater or equal
absorption of ketorolac into the aqueous humor of the eye and includes
carboxymethyl cellulose, allows the solutions of the present invention to
be prepared with no preservative, surfactant and chelating agent. This is
a significant advantage over prior art ketorolac formulations as
preservatives, surfactants and chelating agents can cause irritation to
the eye resulting in less patient compliance and less effectiveness of
prior art ketorolac formulations.

[0035] The term preservative has the meaning commonly understood in the
ophthalmic art. Preservatives are used to prevent bacterial contamination
in multiple-use ophthalmic preparations, and, while not intending to be
limiting, examples include benzalkonium chloride, stabilized oxychloro
complexes (otherwise known as Purite®), phenylmercuric acetate,
chlorobutanol, benzyl alcohol, parabens, and thimerosal. Preferably, the
ketorolac solution of the present invention is preservative free.

[0036] The term surfactant used in this invention has the meaning commonly
understood in the art. Surfactants are used to help solubilize the
therapeutically active agent or other insoluble components of the
composition. Anionic, cationic, amphoteric, zwitterionic, and nonionic
surfactants may all be used in this invention. If a surfactant is
included in the solutions of this invention, preferably, a nonionic
surfactant is used. While not intending to limit the scope of the
invention, some examples of useful nonionic surfactants are polysorbates,
poloxamers, alcohol ethoxylates, ethylene glycol-propylene glycol block
copolymers, fatty acid amides, and alkylphenol ethoxylates, and
phospholipids. Most preferably, the surfactant is an octylphenol
ethoxylate with an average of 40 ethoxylate groups. This type of
surfactant, also known as octoxynol-40 or Igepal CA-897®, can be
purchased under the Igepal CA-897® tradename from Rhone-Poulenc.
Preferably, the ketorolac solution of the present invention is surfactant
free.

[0037] The term chelating agent refers to a compound that is capable of
complexing a metal, as understood by those of ordinary skill in the
chemical art. Chelating agents are used in ophthalmic compositions to
enhance preservative effectiveness. While not intending to be limiting,
some useful chelating agents for the purposes of this invention are
edetate salts like edetate disodium, edetate calcium disodium, edetate
sodium, edetate trisodium, and edetate dipotassium. Preferably, the
ketorolac solution of the present invention is chelator free.

[0038] In addition to surfactants, preservatives, and chelating agents,
tonicity agents and other excipients are often used in ophthalmic
compositions. Tonicity agents are often used in ophthalmic compositions
to adjust the concentration of dissolved material to the desired isotonic
range. Tonicity agents are known to those skilled in the ophthalmic art,
and, while not intending to be limiting, some examples include glycerin,
mannitol, sorbitol, sodium chloride, and other electrolytes. Preferably,
the tonicity agent is sodium chloride.

[0041] Unless otherwise specified, all steps in this procedure were
carried out at room temperature. The following procedure was followed in
accordance with the amounts listed in Table 1 below. Purified water was
charged into the main batch vessel. Mixing was initiated to produce a
vortex sufficient to disperse and/or dissolve all product ingredients
without excessive aeration or foam formation. The following components
were added directly into the vortex in order, allowing each to dissolve
before adding the next: sodium chloride, calcium chloride, dihydrate
magnesium chloride, hexahydrate, boric acid, sodium borate, sodium
carboxymethyl cellulose as a an percent aqueous solution comprising
including a mixture of 65% medium molecular weight and 35% high molecular
weight carboxymethyl cellulose. The solution was mixed for no longer than
15 minutes. A specified amount of 1N sodium hydroxide, was then added.
The pH was checked and, if needed, was adjusted to 7.3 with 1N sodium
hydroxide or 1N hydrochloric acid. Ketorolac tromethamine was then added
based on "as is" assay and mixed until completely dissolved based on
visual inspection. When dissolved, the solution pH was again checked and
if needed adjusted to pH 7.3-7.5 (final target pH is 7.4) with 1N sodium
hydroxide or 1N hydrochloric acid. Purified water was then added to bring
the bulk solution to final volume and allowed to mix for at least 15
minutes to ensure uniformity. The solution was then sterile filtered for
use.

[0042] Unless otherwise specified, all steps in this procedure were
carried out at room temperature. The following procedure was followed in
accordance with the amounts listed in Table 2 below. Purified water at
90% of batch size was charged into the main batch vessel. Mixing was
initiated to produce a vortex sufficient to disperse and/or dissolve all
product ingredients without excessive aeration or foam formation. The
following components were added directly into the vortex in order,
allowing each to dissolve before adding the next: sodium chloride,
edetate disodium, octoxynol-40 (as a 70% stock solution) and
benzalkoniurn chloride (as a 10% stock solution). The amount of
benzalkonium chloride added took into account the assay of the stock
solution used. The solution was mixed for no longer than 15 minutes. A
specified amount of 1N sodium hydroxide, 1.85 mL per liter of final bulk
product, was then added. The pH was checked and if needed was adjusted to
10.7-11.0 with 1N sodium hydroxide or 1N hydrochloric acid. Ketorolac
tromethamine was then added based on "as is" assay and mixed until
completely dissolved based on visual inspection. When dissolved, the
solution pH was again checked and if needed adjusted to pH 7.3-7.5 (final
target pH is 7.4) with 1N sodium hydroxide or 1N hydrochloric acid.
Purified water was then added to bring the bulk solution to final volume
and allowed to mix for at least 15 minutes to ensure uniformity. The
solution was then sterile filtered for use.

[0043] This example was prepared according to the procedure of Example 1,
except that hydroxypropyl cellulose was used in place of the sodium
carboxymethyl cellulose in an amount sufficient to provide a viscosity
equivalent to the viscosity of the composition of Example 1.

EXAMPLE 4

[0044] The following composition was manufactured on a volume basis at
ambient temperates from two principal parts. Each part is manufactured
separately and then combined under controlled sequences to form a sterile
bulk product: the first part (Part 1) involves the dissolution of
carboxymethyl cellulose sodium in water followed by bulk heat
sterilization, and the second part (Part 2) involves dissolution of
ketorolac tromethamine and salts in water sterile filtration throng a 0.2
micron membrane into a sterile pressure vessel. The sterile bulk solution
is then clarity filtered through a 20 micron polypropylene membrane
filter into the filling machine reservoir.

[0045] The sterile post-clarity filtered solution is then filled by a UD
filling machine via blow-fill-seal process into UD vials using virgin
LDPE resin without colorant. The filling is done in an ISO Class 5
environment. The nominal fill is 0.4 mL into 0.9 mL capacity vials.

[0046] Comparison of Aqueous Humor Ketorolac Pharmacokinetics Following a
Single Ocular Instillation of 0.45% Ketorolac Tromethamine Formulations
with Varying pH to Acular LS® in New Zealand White Rabbits.

[0047] Study Objectives: [0048] 1) To compare aqueous humor ketorolac
pharmacokinetics following a single ocular instillation of 0.45%
ketorolac tromethamine formulations with varying pH and Acular LS® to
New Zealand White rabbits; [0049] 2) This Example was designed to
determine whether decreasing the pH of the composition would increase the
absorption of ketorolac into the eye; and, [0050] 3) In addition, one arm
of this trial was designed to test the effect of decreasing viscosity of
the composition from 22 cps to 11 cps.

[0051] The specifics of this study are as follows: [0052] Rabbit Aqueous
Humor Ketorolac Concentrations following Administration of Three 0.45%
Ketorolac Tromethamine Formulations and Acular LS

[0054] The sodium carboxymethyl cellulose-containing formulations perform
better than Acular LS® with a relative bioavailability ranging from
133% (0.45% Keto 22 cps pH 7.2) to 202% (0.45% Keto 22 cps pH 6.8).
However, there is not a clear pH effect-because the 0.45% Keto 22 cps pH
7.4 has a relative bioavailability of 153%, although one anomalous result
maybe driving this observation. Nevertheless, the solution having a pH of
6.8 shows the best bioavailability.

EXAMPLE 6

[0055] A multicenter, randomized, double-masked, parallel-group study is
carried out using the 0.4% ketorolac tromethamine formulations of
Examples 2 and 3. The study subjects consisted of 157 patients
(78-79/group) undergoing unilateral PRK surgery. The key inclusion
criteria for the study is that each subject a) is a candidate for
unilateral photorefractive keratectomy surgery (PRK) within 7 days after
the initial visit, b) have best-corrected ETDRS visual acuity of 20/100
or better, and c) is capable of wearing a soft bandage contact lens. Key
exclusion criteria are a history of refractive ocular surgery and
sensitivity to study medication or its vehicle, Tylenol #3®, or
Ocuflox®. The patient demographics are shown in Table 6. A total of
157 patients are enrolled with an age range of 20-66 years. There are no
significant demographic differences between treatment groups.

[0056] Each subject receives the Ocuflox® 5 min prior to study
medication. The study subjects then receive ketorolac tromethamine 0.4%
ophthalmic solution of Example 2 or Example 3, 1 drop QID for up to 4
days. Then all subjects are then instructed to take Tylenol #3® as
needed for intolerable pain (escape medication). Patients use electronic
diaries with date and time stamp to record the ocular pain they
experience as one of the following: no pain; mild; moderate; severe; and
intolerable.

[0057] The pain intensity is less for the subjects who receive the
solution of Example 2 during the first 12 hours post-PRK compared to
those who receive the solution of Example 3. In particular, during the
first 12 hours post-PRK, the group that receive the solution of Example 2
had fewer patients with severe or intolerable pain compared with the
receive the solution of Example 3. In particular, the median pain
intensity reported by the group which receive the solution of Example 2
was 1 grade less than with the group which receive the solution of
Example 3 (moderate vs. severe on a 5-point scale of 0=no pain to
4=intolerable pain). Additionally, pain intensity is also less for the
group which receive compared with the group which receive the solution of
Example 3.

[0058] This clinical study shows that the solution of invention provides a
greater degree of absorption of ketorolac as compared to the solution
without sodium carboxymethyl cellulose despite the fact that the
solutions have the same concentration of ketorolac and are at the same
viscosity.

[0066] As shown in FIGS. 1-5, Example 7 shows there is an: [0067] 1)
Increase in relative bioavailability of ketorolac as compared to Acular
LS®; [0068] 2) Increased ketorolac concentrations are maintained
longer post-dose; and [0069] 3) Together these data support a reduction
in dosing frequency from 4×/day to 2×/day. As shown in FIG.
6, Acular 0.45% is safe and well-tolerated among human patients when
given 5 times over a half-day and compares very favorably to ACULAR LS.

Visual Acuity in Operative Eye

[0070] This summary of clinical safety (SCS) is based on 2 completed phase
3 studies of identical design and on one completed phase 1 study. All 3
studies support the safe use of a new formulation of ketorolac
tromethamine ophthalmic solution 0.45% w/v (henceforth referred to as
ketorolac 0.45%), an unpreserved formulation of ketorolac tromethamine
ophthalmic solution containing a mixture of medium and high-molecular
carboxymethyl cellulose (CMC). The formulation was used in the phase 3
studies, which investigated the safety of ketorolac 0.45% in cataract
surgery patients. The phase 1 study investigated the safety of ketorolac
0.45% in healthy adult volunteers.

[0071] The current labeling for approved formulations of ketorolac
tromethamine ophthalmic solution such as ACULAR LS® (0.40% w/v
ketorolac) lists from 20% to 40% transient stinging and burning on
instillation. The 0.45% formulation used in the phase 3 studies that form
the basis of this application was developed, among other reasons, to
improve comfort when administered in the eye, primarily by the addition
of medium and high molecular weight carboxymethyl cellulose and the
removal of octoxynol and benzalkonium chloride (BAK).

[0072] Studies evaluated efficacy and safety of ketorolac 0.45% compared
with vehicle (same composition without the active) for the treatment of
anterior chamber inflammation, ocular pain, and inhibition of surgically
induced miosis following cataract extraction with posterior chamber
intraocular lens (IOL) implantation. Both studies demonstrated that
ketorolac 0.45% was safe and well tolerated. No new or unexpected safety
findings were observed in either study. In addition, ketorolac 0.45% was
found to be very well tolerated with a very low incidence of burning and
stinging.

[0073] Another study assessed the safety and tolerability of ketorolac
tromethamine ophthalmic solutions 0.35% and 0.45% compared with ACULAR
LS® 0.4% in healthy adult subjects. ACULAR LS® 0.4% was chosen
for comparison as it was known to be a better tolerated formulation than
original ACULAR® (0.50% w/v ketorolac) due to the lower concentration
of ketorolac and removal of BAK and octoxynol. Compared with ACULAR
LS® 0.4%, ketorolac 0.45% had a consistently lower incidence of
ocular symptoms such as burning/stinging and ocular discomfort when dosed
5 times in 1 day. No new or unexpected safety findings were observed for
any of the ketorolac formulations.

[0074] The ketorolac 0.45% formulation of the present invention was
characterized in ocular and systemic ketorolac rabbit pharmacokinetic and
toxicokinetic studies, in addition to 1-day ocular tolerability, 1-month
ocular toxicity, and 6-day ocular wound healing studies. From the results
of these preclinical studies, 0.45% ketorolac tromethamine administered
twice per day was anticipated to deliver ketorolac to ocular tissues that
are efficacious but at lower levels than those previously demonstrated to
be safe in long term toxicology studies.

[0075] The phase 3 studies were of identical design, multi-center,
randomized, double-masked, parallel group comparison studies conducted to
assess the safety and efficacy of ketorolac 0.45% compared with vehicle.
Study patients underwent cataract extraction surgery with posterior
chamber IOL implantation. Ketorolac 0.45% or vehicle was
self-administered by patients (1 drop twice daily in the operative eye
beginning on the day before surgery and continuing on the day of surgery
through the first 2 weeks following surgery) and administered by medical
personnel (3 drops during the 2 hr prior to surgery and 1 drop after
surgery). The safety parameters assessed were adverse events, vital
signs, intraocular pressure, visual acuity, biomicroscopy, and
ophthalmoscopic examinations. The studies consisted of 7 scheduled
visits: screening (week -4 to day -2); randomization (day -3 to day -1);
cataract surgery day; and postoperative days 1, 3, 7, and 14. Patients
receiving ketorolac 0.45% had a lower incidence of ocular adverse events
and of adverse events that led to discontinuation than patients receiving
vehicle.

[0077] In a two phase 3 studies pooled, more than 2/3 of patients in both
treatment groups experienced at least 1 line of improvement in visual
acuity from baseline to final evaluation. Two patients in each treatment
group had a decrease in visual acuity of >3 lines (0.6% [2/320] of
ketorolac 0.45% patients, 1.3% [2/158] of vehicle patients).

[0078] The proportion of ketorolac 0.45%-treated patients who experienced
at least 3 lines of improvement was statistically significantly higher
than the proportion of vehicle-treated patients (58.1% [186/320] of
ketorolac 0.45% patients, 41.1% [65/158] of vehicle patients,
p<0.001). Statistical significance for the same comparison was
observed in study -006 (p=0.002) but borderline significant in study -005
(p=0.054).

[0079] In the phase 1 study, most subjects had no change in visual acuity
during treatment. Decreases in visual acuity during treatment with
respect to baseline were observed for 1 (5.0%) ketorolac 0.45%-treated
eye, 1 (5.3%) ketorolac 0.35%-treated eye, and 3 (7.7%) ACULAR
LS®-treated eyes.

[0080] Conclusions: [0081] 1) The impact of treatment on visual acuity
favors ketorolac over vehicle; [0082] 2) More than 2/3 of patients in
both treatment groups experienced at least 1 line of improvement in
visual acuity from baseline to final evaluation; [0083] 3) Twice the
percentage of patients in the vehicle group experienced a decrease in
visual acuity of >3 lines; and, [0084] 4) The ketorolac 0.45% w/v
group experienced over 40% greater incidence of patients experiencing at
least 3 lines of improvement--a statistically significant difference.

[0085] The present invention is not to be limited in scope by the
exemplified embodiments, which are only intended as illustrations of
specific aspects of the invention. Various modifications of the
invention, in addition to those disclosed herein, will be apparent to
those skilled in the art by a careful reading of the specification,
including the claims, as originally filed. It is intended that all such
modifications will fall within the scope of the appended claims.

Patent applications by Chin-Ming Chang, Tustin, CA US

Patent applications by Devin F. Welty, Foothill Ranch, CA US

Patent applications by Eldon Q. Farnes, Laguna Beach, CA US

Patent applications by Mayssa Attar, Placentia, CA US

Patent applications by Rhett M. Schiffman, Laguna Beach, CA US

Patent applications by Richard S. Graham, Irvine, CA US

Patent applications in class Ring nitrogen is shared by the cyclos of the bicyclo ring system

Patent applications in all subclasses Ring nitrogen is shared by the cyclos of the bicyclo ring system